DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 11/12/2025, in which claims 1-20, 22, and 24-30 are canceled.
Claims 21, 23, and 31-35 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/JP2018/030666 filed on 08/20/2018.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 11/12/2025, with respect that claims 24-25 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention has been fully considered and is persuasive, as claims 24-25 have been canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 11/12/2025, with respect that claims 24-25 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement has been fully considered and is persuasive, as claims 24-25 have been canceled. This rejection has been withdrawn.
The following are maintained grounds of rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21, 23, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Ellinghuysen et al (US 2007/0243218; IDS 08/10/2021) in view Calbiochem (2006; PTO-892 04/14/2022) and Ditter et al (J. Pharm. Sci., 2018; PTO-892 09/19/2023).
Ellinghuysen discloses pentosan polysulfate (PPS) formulations for treating osteoarthritis, interstitial cystitis, and other conditions of mammals (abstract). The compositions may be administered by injection [0078]. The compositions of Ellinghuysen have improved resistance to degradation and discoloration and improved stability [0001]. Ellinghuysen teaches that the formulations are stable without refrigeration (claim 1) and may remain stable for about 5 years ([0012] and claim 6). Ellinghuysen provides an example in which samples stored at 40° C. and 75% relative humidity are stable [0133]. Ellinghuysen teaches that stable solutions exhibit substantially no discoloration [0054]. Ellinghuysen teaches that degradation products are molecules resulting from a chemical change in the composition brought about over time or by the action of factors including light, temperature, pH, or water, or by reaction with an excipient and/or the immediate container/closure system [0050]. Ellinghuysen further teaches that formulations with a more physiologically compatible pH range are expected to be non-irritating when injected [0115]. Ellinghuysen teaches that PPS is often formulated as a salt, such as sodium PPS, calcium PPS, or potassium PPS [0056]. Exemplary buffers that may be included in the formulations include, among others, phosphate buffers ([0059] and claim 22). Ellinghuysen further discloses that the concentration of the PPS in solution may be about 25 mg/mL to about 500 mg/mL or about 100 mg/mL to about 250 mg/mL [0013]. Ellinghuysen further teaches that the PPS may be formulated with a buffer concentration of 1 to 100 mM [0064]. A suitable pH is between 4 and 8 [0067], and in an exemplary formulation the pH is about 5.8 to about 6.2 [0071]. Thus, Ellinghuysen suggests a pharmaceutical composition comprising 100 mg/mL PPS, with a pH 5.8. Ellinghuysen teaches that the PPS formulation may be lyophilized and further discloses reconstitution of PPS with a sterile aqueous diluent ([0067] and Table 1).
Ellinghuysen does not provide a single embodiment having a sodium phosphate buffer with the recited amounts of the phosphate components and is silent regarding delamination when the lyophilized preparation is reconstituted (instant claim 21).
Calbiochem demonstrates that it is well known to use phosphate buffers with a sodium counterion in biological and physiological solutions (pages 18-20). Calbiochem teaches the preparation of a 100 mM (0.1 M) phosphate buffer using NaH2PO4 and Na2HPO4. Following this recipe using (1) [NaH2PO4][H2O]2 (MW: 156 g/mol) and (2) [Na2HPO4][H2O]12 (MW: 358 g/mol), one would start with solutions comprising 15.6 g/L of (1) and 35.8 g/L of (2).
To prepare a suggested composition of Ellinghuysen with a PPS concentration of 100 mg/mL and a pH of 5.8, one would combine 92 mL of (1) and 8 mL of (2) and add 100 mL of water to prepare the buffer. This would provide 7.18 g/mL of [NaH2PO4][H2O]2 [calculation: (92 mL x 15.6 mg/mL)/(200 mL) = 7.18 mg/mL] and 1.43 g/mL of [Na2HPO4][H2O]12 [calculation: (8 mL x 35.8 mg/mL)/(200 mL) = 1.43 mg/mL]. The overall ratio of pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate in this composition would be 100:1.43:7.18 which is equivalent to 1,000:14.3:71.8. Thus, Ellinghuysen suggests a pharmaceutical composition comprising 100 mg/mL PPS, with a pH 5.8. Calbiochem teaches the preparation of a sodium phosphate buffer as an additive in biological compositions. Applying the buffer recipe of Calbiochem to provide the buffered solution of Ellinghuysen would result in a composition comprising PPS, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate in a ratio of 1,000:14.3:71.8.
Ditter compares various types of vials to evaluate the differences in their risk of delamination under stress (abstract). Ditter further teaches that the presence of glass particles is a well-known phenomenon and problem that has led to product recalls of parenteral products (page 624, paragraph 1). It is known that freezing and thawing place stress on the vial, so lyophilized products would be of higher concern for delamination (page 625, paragraph 1). Another factor leading to delamination is the storage of solutions leading to the enhanced concentration of glass elements in the formulation ((page 624, paragraph 2). Ditter discloses subjecting a number of vials to aggressive delamination screening and establishes that of the ones tested, TopLyo™ is the most durable and resistant to delamination upon contact with a solution under stringent conditions (paragraph bridging pages 628-629 and Figure 2).
It would have been prima facie obvious prepare the lyophilized composition of Ellinghuysen using the buffer of Calbiochem and the vials of Ditter and furthermore to optimize the ratio of PPS, and the buffer components disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate in the composition of Ellinghuysen and Calbiochem because Ellinghuysen teaches that the pH of the composition affected the formation of degradation products and the irritation in a patent when the composition is injected. Ellinghuysen and Calbiochem thus teach that the ratio is a result effective variable such that one of ordinary skill in the art would be motivated to optimize the ratio beginning with a ratio of 1,000:14.3:71.8 in order to minimize the formation of degradation products and irritation caused by injection of the composition. Thus Ellinghuysen in view of Calbiochem suggests the ratio of instant claim 21. Furthermore, one of ordinary skill in the art would have been motivated to use the vials of Ditter in the preparation of the composition of Ellinghuysen and Calbiochem to achieve the desirable outcome of a lyophilized product that does not have delamination contaminants from the lyophilization process.
With respect to instant claim 35, Ellinghuysen suggests the inclusion of a buffer and does not require any other particular components, so it would be further obvious to prepare a lyophilized product consisting of PPS and a buffer, wherein the lyophilization is carried out using a durable vial, resistant to delamination, such as a TopLyo™. In doing so, the artisan would expect a product wherein the generation of particles due to delamination upon reconstitution is avoided.
Claims 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Ellinghuysen et al (US 2007/0243218; IDS 08/10/2021) in view of Jadhav et al (World J. Ph. Pharm. Sci., 2015; PTO-892 10/18/2022), Ditter et al (J. Pharm. Sci., 2018; PTO-892 09/19/2023), and Smith et al (J. Pharm. Sci., 2011; PTO-892 04/14/2022).
Ellinghuysen discloses pentosan polysulfate (PPS) formulations for treating osteoarthritis, interstitial cystitis, and other conditions of mammals (abstract). The compositions of Ellinghuysen have improved resistance to degradation and discoloration and improved stability [0001]. Ellinghuysen further discloses that the concentration of the PPS in solution may be about 25 mg/mL to about 500 mg/mL [0013]. Ellinghuysen states that the formulations may be lyophilized to create a lyophilized dosage form using techniques apparent to one of ordinary skill in the art [0067].
Ellinghuysen does not teach a method of lyophilization of a composition comprising PPS and is silent regarding delamination (instant claims 31-32).
Jadhav discusses the use of lyophilization in the pharmaceutical industry. Jadhav teaches characteristics of lyophilized products, including sterility and stability (pages 1907-1908). The lyophilization process is one comprising three major stages, freezing, primary drying, and secondary drying (page 1906, paragraph 1). Jadhav exemplifies a typical temperature curve having a freezing step at about -40 °C for about 1 hour, a primary drying step at -20 °C for about 20 hours, and a secondary drying step at 30 °C for about 5 hours (page 1913 and Figure 4). Jadhav also reports processes in which the secondary drying is performed at 40 °C and teaches that the secondary drying temperature can be optimized to improve sample stability (paragraph bringing pages 1920-1921). Jadhav teaches that primary drying is the step in which the majority of the water is removed from the product by sublimation (page 1914, paragraph 2) and is complete when all frozen bulk water is removed via sublimation (page 1916, paragraph 1). Jadhav further teaches that the freezing step may include an annealing step (page 1914, paragraph 1). Jadhav further discusses specialized vials for lyophilization, such as TopLyo™, which has a customized geometry and a hydrophobic inner layer to maximize strength, minimize breakage and improve heat transfer and cake aesthetics (page 1924, paragraphs 1-2).
Smith describes the process of annealing in the freezing step of lyophilization wherein the temperature of a frozen sample is raised and held at a sub-freezing point for a period of time and then returned to the freezing temperature (Table 1). This process reduces primary drying time (page 1799, paragraph 3). Smith further discusses optimization of the annealing phase, with a typical time of 0.5 to 10 hr (page 1800, paragraph 3). For example, Table 1 shows a process having annealing temperatures of -5, -10 and -15 °C which are held for 5 hours after an initial sample freezing and before returning the sample to the freezing temperature for an additional 2 hours. Smith further teaches the determination of the glass transition temperature for a solution (pages 1805-1806). Smith also teaches that aside from the annealing temperature and time, other parameters such as drier type/size, vial type, fill load and solid content are expected to impact the rate and duration of primary drying (paragraph bridging pages 1800-1801).
Ditter compares various types of vials to evaluate the differences in their risk of delamination under stress (abstract). Ditter further teaches that the presence of glass particles is a well-known phenomenon and problem that has led to product recalls of parenteral products (page 624, paragraph 1). It is known that freezing and thawing place stress on the vial, so lyophilized products would be of higher concern for delamination (page 625, paragraph 1). Another factor leading to delamination is the storage of solutions leading to the enhanced concentration of glass elements in the formulation ((page 624, paragraph 2). Ditter discloses subjecting a number of vials to aggressive delamination screening and establishes that of the ones tested, TopLyo™ is the most durable and resistant to delamination upon contact with a solution under stringent conditions (paragraph bridging pages 628-629 and Figure 2).
It would have been prima facie obvious to combine the teachings of Ellinghuysen, Jadhav, Smith, and Ditter before the effective filing date of the claimed invention by lyophilizing the sample of Ellinghuysen according to the methods of Jadhav and Smith in the vial of Ditter to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select a freeze drying process beginning with a freezing step at about -40 °C for about 1 hour followed by a primary drying step at about -20 °C for about 20 hours, and a secondary drying step at about 40 °C for about 5 hours as suggested by Jadhav. It would further have been prima facie obvious to optimize the time of the primary drying step through routine optimization to achieve complete removal of all frozen bulk water via sublimation as taught by Jadhav. In addition, it would have been prima facie obvious to include an annealing step after the initial freezing step comprising raising the temperature to -10 °C for about 5 hours followed by returning to the freezing temperature for 2 hours as taught by Smith in order to reduce primary drying time. Furthermore, it would have been prima facie obvious to optimize the concentration of the PPS in the solution beginning with a concentration in the range of 25 mg/mL to about 500 mg/mL as taught by Ellinghuysen in order to optimize the solid content in the vials and thereby achieve an ideal primary drying rate and duration as taught by Smith. Finally, it would have been prima facie obvious to carry out the lyophilization using a durable vial resistant to delamination, such as a TopLyo™. In doing so, the artisan would expect a product wherein the generation of particles due to delamination is avoided. One of ordinary skill in the art would have a reasonable expectation of success in selecting these lyophilization parameters because Ellinghuysen teaches that the sample may be lyophilized using techniques apparent to one of ordinary skill in the art, and Jadhav, Smith, and Ditter teach techniques known in the art of lyophilization.
Response to Arguments
Applicant’s arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant states that the mass ratio of pentosan polysulfate sodium, disodium hydrogen phosphate, and sodium dihydrogen phosphate of 1000:22:68.4 in the lyophilized preparation is not obvious over the prior art because it would require significant trial and error and would not be a simple optimization of variables (Remarks, page 4, paragraph 5). This is not persuasive.
Applicant has not demonstrated the criticality of the claimed range of compositions having the recited mass ratio of pentosan polysulfate sodium, disodium hydrogen phosphate, and sodium dihydrogen phosphate . As discussed in the above grounds of rejections, Ellinghuysen teaches stable PPS formulations having a concentration of the PPS about 25 mg/mL to about 500 mg/mL with a buffer concentration of 1 to 100 mM and a pH of about 5.8 to about 6.2. The combined teachings of Ellinghuysen and Calbiochem teach that the ratio is a result effective variable such that one of ordinary skill in the art would be motivated to optimize the ratio beginning with a ratio of 1,000:14.3:71.8 in order to minimize the formation of degradation products and irritation caused by injection of the composition.
Applicant provides Exhibit A to show three-year long-term stability test results for the lyophilized preparation (Remarks, Page 5, paragraph 1). Applicant argues that these findings constitute the strongest evidence that delamination does not occur when the lyophilized preparation of the present invention is reconstituted (Remarks, Page 5, paragraph 2). This amounts to an argument from unexpected results. This is not persuasive.
Exhibit A is new data and must be submitted as a declaration in order to be considered for unexpected results. If Exhibit A were submitted in a declaration, it would still be insufficient to overcome the prime facie case of obviousness set forth because it lacks comparison to the closest prior art such that the properties of the claimed invention are shown to be different compared to the prior art. Furthermore, the claimed invention is not commensurate in scope with this data. The example disclosed does not represent a representative number of species of preparations to cover the vast number of preparations that are claimed when the mass ratio of the pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate is limited to that recited in instant claim 21 but the preparation can occur at any temperatures and over any time frame and may be reconstituted at any concentration. MPEP 716.02(b) states that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
Applicant continues to argue regarding instant claims 31-32 that the amendment to specify 50 mg/mL makes the claim commensurate in scope with the showing of unexpected results in the declaration filed 05/28/2024. The unexpected results have been reported as being the formation of a clean cake separated from the inner surface of the vial such that delamination does not occur when the lyophilized preparation is reconstituted. Applicant now argues that Table 1 indicates these stability results as showing that invisible minute particles were detected in the reconstituted solution under accelerated conditions, and there was no increase in the count of very small particles not observable to the naked eye (Remarks, paragraph bridging page 4-5 and page 5, paragraph 6 to page 6, paragraph 1). This is not persuasive.
There are no comparative example to show that this effect is due to the claimed features of the instant invention and thereby show that this data constitutes unexpected results. MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693